The overall goal of this proposal is to investigate the neural mechanisms underlying oral irritation produced by common irritant chemicals in foods, beverages and other consumer products. A multidisciplinary experimental approach will address the hypothesis that neurons in the trigeminal pain pathway in a rodent model signal oral irritation in a manner that correlates with human perception. Specific aims are as follows. Specific Aim 1. To investigate the distinct patterns of sensation elicited by different irritant chemicals in human subjects. Repetitive or continual intraoral application of certain irritants (capsaicin, concentrated NaC1) elicits irritation that progressively increases in intensity (sensitization), while irritation elicited by other irritants (nicotine menthol) declines (desensitization). We will study if additional irritant chemicals (acids, mustard oil, CO2) can be categorized as sensitizing or desensitizing. We will also investigate interactions between irritants (e.g., cross-desensitization), and if humans can qualitatively discriminate between irritants independent of taste or smell cues. Specific Aim 2. To investigate neural mechanisms of oral irritation, by recording responses of single nociceptive neurons in subnucleus caudalis (Vc) to lingual application of irritant chemicals in rats. We will determine if the irritant-evoked Vc neuronal firing pattern correlates with the pattern of human sensory ratings. Capsaicin and other sensitizing agents are predicted to elicit a progressive increase in firing, while a progressive decline in firing is predicted for nicotine and other desensitizing agents. Additional goals are to test if "chemo- selective" Vc neurons exist, and if interneurons and ascending projection neurons in Vc have similar or different properties. Specific Aim 3. To investigate transduction mechanisms, by determining if chemically-evoked irritant sensation, or activation of Vc neurons, is reduced by specific antagonists. We will focus on neuronal nicotinic receptors, amiloride-sensitive ion channels, vanilloid (VR-1) receptors, and the Na-/H- membrane exchange pump. Vc activity will be measured by single-unit recording and by c-fog immunohistochemistry. Specific Aim 4. To develop a rodent model of oral irritation, using a paired preference paradigm to measure consumption of water vs. an aqueous solution of capsaicin. We hypothesize that detectable concentrations of capsaicin will be rejected. This model will be used to investigate the role of the neuropeptide, substance P, in oral irritation. Specific Aim 5. To test the hypothesis that intraoral irritants reduce human judgments of the intensity of taste qualities using a sensitive 2-alternative forced-choice paradigm. In a corresponding animal study, we will determine if responses of neurons in the n. tractus solitarius (NTS), a taste relay, are reduced by intraoral capsaicin